Emerging biological roles of Cl− intracellular channel proteins

Abstract

Cl− intracellular channels (CLICs) are a family of six evolutionary conserved cytosolic proteins that exist in both soluble and membraneassociated forms; however, their functions have long been elusive. Soluble CLICs adopt a glutathione S-transferase (GST)-fold, can induce ion currents in artificial membranes and show oxidoreductase activity in vitro, but there is no convincing evidence of CLICs having such activities in vivo. Recent studies have revealed a role for CLIC proteins in Rho-regulated cortical actin dynamics as well as vesicular trafficking and integrin recycling, the latter of which are under the control of Rab GTPases. In this Commentary, we discuss the emerging roles of CLIC proteins in these processes and the lessons learned from genetargeting studies. We also highlight outstanding questions regarding the molecular function(s) of these important but still poorly understood proteins.

Three Decades of Chloride Intracellular Channel Proteins: From Organelle to Organ Physiology

“…Contained in this overview is a summary of key findings made during the past decade on CLICs. For information on other chloride channels, the reader is directed to some recently published reviews (Argenzio & Moolenaar, ; Boedtkjer, Matchkov, Boedtkjer, & Aalkjaer, ; De Felice, ; Elborn, ; Jentsch, ; Miller, ; Ponnalagu et al., ; Sabirov, Merzlyak, Islam, Okada, & Okada, ; Stauber & Jentsch, ).…”

Electrochemical Bromide Sensing with a Halogen Bonding [2]Rotaxane

“…As shown in Scheme 1B, the multistep synthesis of ferrocene-appended XB macrocycle 3.I was achieved by first react- Scheme ing bis(iodoalkyne) 4 and two equivalents of azide 5 via a copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) protocol to form the bis-phenol precursor 6. Subsequent ring-closing was accomplished by Williamson ether synthesis [41] 4 ]PF 6 in CD 2 Cl 2 confirmed that the macrocycle was binding Cu I via the Lewis basic nitrogen atoms of the iodotriazole groups (see Figure S2-1, Supporting Information), a prerequisite for 3.I to be amenable towards CuAAC-AMT rotaxane synthesis. Indeed, a macrocycle containing the 1,3-bis(iodotriazole)benzene motif has been used to synthesise a family of XB rotaxanes by CuAAC-AMT, demonstrating that the benzene-iodotriazoles are conformationally-flexible enough to allow the Cu I to be coordinated in an endotopic fashion facing the interior of the macrocycle's cavity.…”

“…This suggested that although XB interactions were still primarily driving SCNbinding in the vicinity of the rotaxane cavity, the anion was too large to fit completely within it. For SO 4 2-( Figure S3-6, Supporting Information), very small shifts of all rotaxane proton resonances were seen, with the internal pyridinium proton H 1 only moving downfield by +0.03 ppm after addition of 10.0 equivalents of the oxoanion. Despite being capable of the strongest electrostatic attractions with the rotaxane, these results indicated that SO 4 2was interacting very weakly with rotaxane 1, which is probably a consequence of the anion's strong hydration in the aqueous solvent mixture and large size preventing access to the binding cavity.…”

“…For SO 4 2-( Figure S3-6, Supporting Information), very small shifts of all rotaxane proton resonances were seen, with the internal pyridinium proton H 1 only moving downfield by +0.03 ppm after addition of 10.0 equivalents of the oxoanion. Despite being capable of the strongest electrostatic attractions with the rotaxane, these results indicated that SO 4 2was interacting very weakly with rotaxane 1, which is probably a consequence of the anion's strong hydration in the aqueous solvent mixture and large size preventing access to the binding cavity. Monitoring the shifts of internal pyridinium proton H 1 during the course of the titration experiments and fitting the data to a 1:1 stoichiometric hostguest binding model using WinEQNMR2 [42] enabled anion association constants to be determined (Table 1).…”

“…Bromide is pervasive in the biosphere and is present in natural waters typically at concentrations of tens of mg/L Although its physiological roles are currently not as well‐understood as those for chloride and iodide,, bromide has been shown to be essential for tissue development in humans, while excessive quantities can be toxic (> 12 mM), and delay postnatal growth and brain development . In addition, the presence of excessive quantities of bromide in water can affect the efficacy of water treatment processes, and even react with disinfectants to produce toxic brominated by‐products .…”